The prevalence of insulin resistance in glucose intolerant subjects has long been recognized. Reaven et al (American Journal of Medicine 1976, 60, 80) used a continuous infusion of glucose and insulin (insulin/glucose clamp technique) and oral glucose tolerance tests to demonstrate that insulin resistance existed in a diverse group of nonobese, nonketotic subjects. These subjects ranged from borderline glucose tolerant to overt, fasting hyperglycemia. The diabetic groups in these studies included both insulin dependent (IDDM) and noninsulin dependent (NIDDM) subjects.
Coincident with sustained insulin resistance is the more easily determined hyperinsulinemia, which can be measured by accurate determination of circulating plasma insulin concentration in the plasma of subjects. Hyperinsulinemia can be present as a result of insulin resistance, such as is in obese and/or diabetic (NIDDM) subjects and/or glucose intolerant subjects, or in IDDM subjects, as a consequence of over injection of insulin compared with normal physiological release of the hormone by the endocrine pancreas.
The association of hyperinsulinemia with obesity and with ischemic diseases of the large blood vessels (e.g. atherosclerosis) has been well established by numerous experimental, clinical and epidemiological studies (summarized by Stout, Metabolism 1985, 34, 7, and in more detail by Pyorala et al, Diabetes/Metabolism Reviews 1987, 3, 463). Statistically significant plasma insulin elevations at 1 and 2 hours after oral glucose load correlates with an increased risk of coronary heart disease.
Since most of these studies actually excluded diabetic subjects, data relating the risk of atherosclerotic diseases to the diabetic condition are not as numerous, but point in the same direction as for nondiabetic subjects (Pyorala et al). However, the incidence of atherosclerotic diseases in morbidity and mortality statistics in the diabetic population exceeds that of the nondiabetic population (Pyorala et al; Jarrett Diabetes/Metabolism Reviews 1989,5, 547; Harris et al, Mortality from diabetes, in Diabetes in America 1985).
The independent risk factors obesity and hypertension for atherosclerotic diseases are also associated with insulin resistance. Using a combination of insulin/glucose clamps, tracer glucose infusion and indirect calorimetry, it has been demonstrated that the insulin resistance of essential hypertension is located in peripheral tissues (principally muscle) and correlates directly with the severity of hypertension (DeFronzo and Ferrannini, Diabetes Care 1991, 14, 173). In hypertension of the obese, insulin resistance generates hyperinsulinemia, which is recruited as a mechanism to limit further weight gain via thermogenesis, but insulin also increases renal sodium reabsorption and stimulates the sympathetic nervous system in kidneys, heart, and vasculature, creating hypertension.
It is now appreciated that insulin resistance is usually the result of a defect in the insulin receptor signaling system, at a site post binding of insulin to the receptor. Accumulated scientific evidence demonstrating insulin resistance in the major tissues which respond to insulin (muscle, liver, adipose), strongly suggests that a defect in insulin signal transduction resides at an early step in this cascade, specifically at the insulin receptor kinase activity, which appears to be diminished (reviewed by Haring, Diabetalogia 1991, 34, 848).
Protein-tyrosine phosphatases (PTPases) play an important role in the regulation of phosphorylation of proteins. The interaction of insulin with its receptor leads to phosphorylation of certain tyrosine molecules within the receptor protein, thus activating the receptor kinase. PTPases dephosphorylate the activated insulin receptor, attenuating the tyrosine kinase activity. PTPases can also modulate post-receptor signaling by catalyzing the dephosphorylation of cellular substrates of the insulin receptor kinase. The enzymes that appear most likely to closely associate with the insulin receptor and therefore, most likely to regulate the insulin receptor kinase activity, include PTP1B, LAR, PTPxcex1 and SH-PTP2 (B. J. Goldstein, J. Cellular Biochemistry 1992, 48, 33; B. J. Goldstein, Receptor 1993, 3, 1-15,; F. Ahmad and B. J. Goldstein Biochim. Biophys Acta 1995, 1248, 57-69).
McGuire et al. (Diabetes 1991, 40, 939), demonstrated that nondiabetic glucose intolerant subjects possessed significantly elevated levels of PTPase activity in muscle tissue vs. normal subjects, and that insulin infusion failed to suppress PTPase activity as it did in insulin sensitive subjects.
Meyerovitch et al (J. Clinical Invest. 1989, 84, 976) observed significantly increased PTPase activity in the livers of two rodent models of IDDM, the genetically diabetic BB rat, and the STZ-induced diabetic rat. Sredy et al (Metabolism, 44, 1074, 1995) observed similar increased PTPase activity in the livers of obese, diabetic ob/ob mice, a genetic rodent model of NIDDM.
The compounds of this invention have been shown to inhibit PTPases derived from rat liver microsomes and human-derived recombinant PTPase-1B (hPTP-1B) in vitro. They are useful in the treatment of insulin resistance associated with obesity, glucose intolerance, diabetes mellitus, hypertension and ischemic diseases of the large and small blood vessels.
B. Reidl, et al. (EP 693491A1) disclosed the oxazolodinone A as an antibacterial agent. 
A. Bridges, et al. (EP 568289A2) disclosed the thienothiopheneamidine B as a urokinase inhibitor. 
H. -M. Chen, et al., Indian J. Chem.,Sect. B: Org. Chem. Include. Med. Chem. 1996, 35B(12), 1304-1307 disclosed compound C. 
N. R. Guirguis, et al., J. Prakt. Chem. 1990, 332(3), 414-418 disclosed compound D. 
N. R. Guirguis, et al., Liebigs Ann. Chem. 1986, 1003-1011 disclosed benzothiophenes E. Also M. C. Dubroeucq et al., (EP 248734A1) dosclosed E (R1xe2x95x90CO2H) as an anxiolytic. 
T. Kuroda, et al., J. Org. Chem. 1994, 59, 7353-7357 and J. Chem. Soc., Chem. Commun. 1991, 1635-1636 disclosed benzothiophenes F. 
A. I. Hashem, J. Prakt. Chem. 1977, 319, 689-692 disclosed benzofuran G. 
Y. Akao, et al., Jpn. Kokai Tokkyo Koho JP 04016854 A2(Japanese patent, CA: 117:36570) disclosed six compounds containing the 4-aryl-naphtho[2,3-b]thiophene ring system. These compounds were cyclobutenediylium dimers of that ring, system made as electrophotographic photoreceptors. One typical example is shown by structure H below. 
J. P. Konopelski, et al., Synlett 1996, 609-611 disclosed indole I. 
P. Molina, et al, Tetrahedron, 1994, 50, 5027-36 and Tetrahedron Lett., 1993, 34, 2809-2812 disclosed indole derivatives J. 
A. Napolitano, et al., Tetrahedron 1989, 45, 6749-60 disclosed indole K. 
G. Dryhurst, et al., J. Am. Chem. Soc. 1989, 111, 719-726 disclosed compound L. 
M. d""Ischia, et al., Tetrahedron 1987, 43, 431-434 disclosed compound M. 
This invention provides a compound of formula I having the structure 
A is hydrogen, halogen, or OH;
B and D are each, independently, hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12 carbon atoms, cycloalkyl of 3-8 carbon atoms, nitro, amino, xe2x80x94NR1R1a, xe2x80x94NR1COR1a, xe2x80x94NR1CO2R1a, cycloalkylamino of 3-8 carbon atoms, morpholino, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, xe2x80x94COR1b or OR;
R is hydrogen, alkyl of 1-6 carbon atoms, xe2x80x94COR1, xe2x80x94(CH2)nCO2R1, xe2x80x94CH(R1a)CO2R1, xe2x80x94SO2R1, xe2x80x94(CH2)mCH(OH)CO2R1, xe2x80x94(CH2)mCOCO2R1, xe2x80x94(CH2)mCHxe2x95x90CHCO2R1, or xe2x80x94(CH2)mO(CH2)oCO2R1;
R1 is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl, or CH2CO2R1xe2x80x2;
R1xe2x80x2 is hydrogen or alkyl of 1-6 carbon atoms
E is S, SO, SO2, O, or NR1c;
X is hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, CN, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aryloxy; arylalkoxy, nitro, amino, NR2R2a, NR2COR2a, cycloalkylamino of 3-8 carbon atoms, morpholino, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl, xe2x80x94OCH2CO2R2b or xe2x80x94COR2c;
Y is hydrogen, halogen, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12 carbon atoms, xe2x80x94OR3, SR3, NR3R3a, xe2x80x94COR3b, morpholine or piperidine;
R1a, R1c, R2, R2a R3, R3a are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, or aryl;
R1b is alkyl of 1-6 carbon atoms or aryl;
R2b is hydrogen, alkyl of 1-6 carbon atoms;
R2c and R3b are each, independently, alkyl of 1-6 carbon atoms, aryl, or aralkyl of 6-12 carbon atoms;
C is hydrogen, halogen or OR4;
R4 is hydrogen, alkyl of 1-6 carbon atoms,xe2x80x94CH(R5)W, xe2x80x94C(CH3)2CO2R6, 5-thiazolidine-2,4-dione, xe2x80x94CH(R7)(CH2)mCO2R6, xe2x80x94COR6, xe2x80x94PO3(R6)2, xe2x80x94SO2R6, xe2x80x94(CH2)pCH(OH)CO2R6, xe2x80x94(CH2)pCOCO2R6, xe2x80x94(CH2)pCHxe2x95x90CHCO2R6, or xe2x80x94(CH2)pO(CH2)qCO2R6;
R5 is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl, xe2x80x94CH2(1H-imidazol-4-yl), xe2x80x94CH2(3-1H-indolyl), xe2x80x94CH2CH2(1,3-dioxo-1,3-dihydro-isoindol-2-yl), xe2x80x94CH2CH2(1-oxo-1,3-dihydro-isoindol-2-yl), xe2x80x94CH2(3-pyridyl), xe2x80x94CH2CO2H, or xe2x80x94(CH2)nG;
G is NR6aR7a, NR6aCOR7a, 
W is CO2R6, CONH2, CONHOH, CN, CONH(CH2)2CN, 5-tetrazole, xe2x80x94PO3(R6)2, xe2x80x94CH2OH, xe2x80x94CONR6bCHR7b, xe2x80x94CH2NR6bCHR7bCO2R6, xe2x80x94CH2OCHR7bCO2R6 xe2x80x94CH2Br, or xe2x80x94CONR6bCHR7bCO2R6;
R6, R6a, R7, R7a are each, independently, is hydrogen, alkyl of 1-6 carbon atoms, or aryl;
R6b is hydrogen or xe2x80x94COR6c;
R6c is alkyl of 1-6 carbon atoms or aryl;
R7b is hydrogen, alkyl of 1-6 carbon atoms, or hydroxyalkyl of 1-6 carbon atoms;
Z1 and Z2 are each, independently, hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, cycloalkyl of 3-8 carbon atoms, nitro, amino, xe2x80x94NR1R1a, xe2x80x94NR1COR1a, cycloalkylamino of 3-8 carbon atoms, morpholino, or OR8, or Z1 and Z2 may be taken together as a diene unit having the formula xe2x80x94CHxe2x95x90CR9xe2x80x94CR10xe2x95x90CR11xe2x80x94;
R8 is hydrogen, alkyl of 1-6 carbon atoms, or aryl;
R9, R10, and R11 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aryl, halogen, hydroxy, or alkoxy of 1-6 carbon atoms
m is 1 to 4
n is 1 or 2;
p is 1 to 4;
q is 1 to 4;
or a pharmaceutically acceptable salt thereof, which are useful in treating metabolic disorders related to insulin resistance or hyperglycemia.
Pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids when a compound of this invention contains a basic moiety, such as when R5 is CH2(3-pyridyl), or Y is morpholine or contains similar basic moieties. Salts may also be formed from organic and inorganic bases, preferably alkali metal salts, for example, sodium, lithium, or potassium, when a compound of this invention contains a carboxylate or phenolic moiety.
Alkyl includes both straight chain as well as branched moieties. Halogen means bromine, chlorine, fluorine, and iodine. It is preferred that the aryl portion of the aryl or aralkyl substituent is a phenyl or naphthyl; with phenyl being most preferred. The aryl moiety may be optionally mono-, di-, or tri- substituted with a substituent selected from the group consisting of alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, trifluoromethyl, halogen, alkoxycarbonyl of 2-7 carbon atoms, alkylamino of 1-6 carbon atoms, and dialkylamino in which each of the alkyl groups is of 1-6 carbon atoms, nitro, cyano, xe2x80x94CO2H, alkylcarbonyloxy of 2-7 carbon atoms, and alkylcarbonyl of 2-7 carbon atoms.
The compounds of this invention may contain an asymmetric carbon atom and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry in Formula I, the present invention includes such optical isomers and diastereomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.
The compounds of this invention may be atropisomers by virtue of possible restricted or slow rotation about the aryl-tricyclic or aryl-bicyle single bond. This restricted rotation creates additional chirality and leads to enantiomeric forms. If there is an additional chiral center in the molecule, diasteriomers exist and can be seen in the NMR and via other analytical techniques. While shown without respect to atropisomer stereochemistry in Formula I, the present invention includes such atoropisomers (enantiomers and diastereomers; as well as the racemic, resolved, pure diastereomers and mixutures of diasteomers) and pharmaceutically acceptable salts thereof.
Preferred compounds of this invention include compounds of formula (I), having the structure 
wherein
A is hydrogen or halogen
B and D are each, independently, hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, branched alkyl, cycloalkyl of 3-8 carbon atoms, nitro or OR;
R is hydrogen or alkyl of 1-6 carbon atoms;
E is S, or O;
X is hydrogen, halogen, alkyl of 1-6 carbon atoms, CN, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aryloxy; arylalkoxy, nitro, amino, NR2R2a, NR2COR2a, cycloalkylamino, morpholino, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl;
R1, R1a, R2, R2a, R3, and R3a are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, or aryl;
Y is hydrogen, halogen, OR3, SR3, NR3R3a or morpholine;
C is hydrogen, halogen, or OR4;
R4 is hydrogen, alkyl of 1-6 carbon atoms, xe2x80x94CH(R5)W, xe2x80x94C(CH3)2CO2R6, 5-thiazolidine-2,4-dione, xe2x80x94CH(R7)(CH2)mCO2R6, xe2x80x94COR6, xe2x80x94PO3(R6)2, xe2x80x94SO2R6, xe2x80x94(CH2)pCH(OH)CO2R6, xe2x80x94(CH2)pCOCO9R6, xe2x80x94(CH2)pCHxe2x95x90CHCO2R6, or xe2x80x94(CH2)pO(CH2)qCO2R6;
R5 is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl, xe2x80x94CH2(1H-imidazol-4-yl), xe2x80x94CH2(3-1H-indolyl), xe2x80x94CH2CH2(1,3-dioxo-1,3-dihydro-isoindol-2-yl), xe2x80x94CH2CH2(1-oxo-1,3-dihydro-isoindol-2-yl), or xe2x80x94CH2(3-pyridyl);
W is CO2R6, xe2x80x94CONH2, xe2x80x94CONHOH, or 5-tetrazole, or xe2x80x94CONR6bCHR7bCO2R6;
R6, R6a, R6b,R7, R7a, and R7b are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or aryl;
Z1 and Z2 are each, independently, hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, cycloalkyl of 3-8 carbon atoms, nitro, amino, xe2x80x94NR1R1a, xe2x80x94NR1COR1a, cycloalkylamino of 3-8 carbon atoms, morpholino, or OR8, or Z1 and Z2 may be taken together as a diene unit having the formula xe2x80x94CHxe2x95x90CR9-CR10xe2x95x90CHxe2x80x94;
R9 and R10 are independently, hydrogen, or alkyl of 1-6 carbon atoms;
p is 1 to 4;
q is 1 to 4;
or a pharmaceutically acceptable salt thereof.
More preferred compounds of this invention include compounds of formula (I), having the structure 
wherein
A is hydrogen;
B and D are each, independently, halogen, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, or cycloalkyl of 3-8 carbon atoms;
E is S or O;
X is hydrogen, halogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, CN, alkoxy of 1-6 carbon atoms, aryloxy, arylalkoxy of 6-12 carbon atoms, arylsulfanyl;
Y is hydrogen or xe2x80x94NR1R2, or morpholine;
R1 and R2 are each, independently, hydrogen or alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, or aryl;
C is OR4;
R4 is hydrogen, alkyl of 1-6 carbon atoms, xe2x80x94CH(R5)W, or 5-thiazolidine-2,4-dione;
R5 is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl, xe2x80x94CH2(3-1H-indolyl), xe2x80x94CH2CH2(1,3-dioxo-1,3-dihydro-isoindol-2-yl), or xe2x80x94CH2CH2(1-oxo-1,3-dihydro-isoindol-2-yl);
W is xe2x80x94CO2R6, xe2x80x94CONH2, xe2x80x94CONHOH, 5-tetrazole, xe2x80x94PO3(R6)2, or xe2x80x94CONR6CHR6CO2R6 
R6 is hydrogen or alkyl of 1-6 carbon atoms;
Z1 and Z2 are taken together as a diene unit having the formula xe2x80x94CHxe2x95x90CHxe2x80x94Hxe2x95x90CHxe2x80x94;
or a pharmaceutically acceptable salt thereof.
Even more preferred compounds of this invention include:
(R)-2-[2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionic acid;
(R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-ethyl-phenoxy]-3-phenyl-propionic acid;
(R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2, 6-dimethyl-phenoxy]-3-phenyl-propionic acid;
(R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-fluoro-phenoxy]-3-phenyl-propionic acid;
[4-(9-bromo-2,3 -dimethyl-naphtho[2,3-b]thiophen-4-yl)-2, 6-diisopropyl-phenoxy]-acetic acid;
(R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-sec-butyl-phenoxy]-3-phenyl-propionic acid;
(R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-isopropyl-phenoxy]-3-phenyl-propionic acid;
(R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-3-phenyl-propionic acid
(R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-isopropyl-phenoxy]-3-phenyl-propionic acid;
(R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-3-phenyl-propionic acid;
(R)-2-[2,6-dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionic acid;
(R)-2-[2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-4-phenyl-butyric acid;
(S)-2-[2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-4-phenyl-butyric acid;
2-[2,6-dibromo-4-(9-bromo-3-methyl-2-morpholin-4-ylmethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionic acid;
(R)-2-[2,6-dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-propionic acid;
[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenoxy]-3-phenyl-propionic acid;
2, 6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol;
2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenol;
(R)-2-[2,6-dibromo-4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionic acid;
(R)-2-[2,6-dibromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-phenoxy]-3-phenyl-propionic acid,
(2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-3-phenyl-propionic acid,
(R)-2-[4-(9-bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionic acid,
{(2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionylamino}-acetic acid;
{(2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionylamino}-acetic acid
or pharmaceutically acceptable salts thereof.
The compounds of this invention can be prepared according to the following schemes from commercially available starting materials or starting materials which can be prepared using to literature procedures. These schemes show the preparation of representative compounds of this invention. 
In Scheme 1, 2, 3-dimethylthiophene (II: E is S) is prepared from commercially available 3-methyl-thiophene-carboxaldehyde using Wolff-Kishner conditions (hydrazine followed by KOH/ethylene glycol reflux). Compound (II: E is S or O) is treated with one to 1.3 molar equivalents of an alkyl lithium reagent such as N-butyl lithium most preferably in a nonprotic solvent such as THF at temperatures ranging from xe2x88x9278xc2x0 C. to room temperature under an inert atmosphere such as nitrogen or argon to provide the 2-lithiated-thiophene or furan derivative. This lithiated analog is reacted in situ with one or more molar equivalents of benzaldehyde, generally at xe2x88x9278xc2x0 C. to room temperature for 5 min to 3 h to provide the compound of formula (III: Q=OH; E is S or O). The hydroxy group (Q=OH) of (III) can be removed by a number of reduction procedures such as hydrogenation using palladium catalysts to produce the compound of formula (III: Q=H; E is S or O) but is most conveniently removed using the method of Nutaitis, et. al. (Org. Prep. and Proceed. Int. 1991, 23, 403-411) in which (III: Q=OH; E is S or O) is stirred with one to ten molar equivalents of sodium borohydride in a suitable solvent such as ether, THF or dichloromethane at 0xc2x0 C. to room temperature and one to fifty molar equivalents of trifluoroacetic acid is slowly added over a 15 min to 3 h period to produce the compound of formula (III: Q=H; E is S or O). Alternatively, the 2-lithiated analog of compound (II: E is S or O) in a nonprotic solvent such as THF can be reacted with one or more molar equivalents of a benzyl halide such as benzyl bromide (PhCH2Br) at xe2x88x9278xc2x0 C. to room temperature to directly provide the compound of formula (III: Q=H; E is S or O).
The compounds of formula (III: Q=H; E is S or O) can be acylated with one or more molar equivalents of a commercially available benzoic acid chloride of formula (IV: A, B, C, D is H or OMe; with the A, B, C, D, combination of substituents having at least one OMe group but not more than three OMe groups) to produce the acylated derivative of formula (V: A, B, C, D is H or OMe; with the A, B, C, D, combination of substituents having at least one OMe group but not more than three OMe groups; E is S or O). This acylation is accomplished most readily using a one to five molar equivalents of a Lewis acid catalyst such as tin tetrachloride or aluminum chloride in an inert solvent such as dichloromethane, 1, 2-dichloroethane or carbon disulfide, generally at temperatures such as xe2x88x9278xc2x0 C. to room temperature.
Cyclization of the compounds of formula (V: A, B, C, D is H or OMe; with the A, B, C, D, combination of substituents having at least one OMe group but not more than three OMe groups; E is S or O) is generally best accomplished using one to ten molar equivalents of a strong Lewis acid such as a trihaloborane, most conveniently tribromoborane. The reaction is best performed at xe2x88x9278xc2x0 C. with warming to room temperature or heating to 50xc2x0 C. in a halocarbon solvent such as dichloromethane under an inert atmosphere such as nitrogen or argon. These procedures not only effect cyclization and aromatization with concomitant loss of water, but also result in demethylation of any pendant methoxy moieties and result in the production of compounds of formula (Ia: A, B, C, D is H or OH; with the A, B, C, D, combination of substituents having at least one OH group but not more than three OH groups; E is S or O).
In an analogous fashion to the reactions above in Scheme 1, the compounds of formula (Ia: A is H; B, D is alkyl of 1-6 carbon atoms or fluoro; C is OH; E is S or O) can be prepared starting from the compound of formula (III: Q is H; E is S or O) and the appropriate benzoic acid chloride (IV: A is H; B, D is alkyl of 1-6 carbon atoms or fluoro; C is OMe). The benzoic acid chloride (IV: A is H; B, D is alkyl of 1-6 carbon atoms or fluoro; C is OMe). is prepared from the corresponding benzoic acid by standard procedures using reagents such as oxalyl chloride and thionyl chloride. The starting benzoic acid of the benzoic acid chloride (IV: A is H; B, D is alkyl of 1-6 carbon atoms or fluoro; C is OMe) is commercially available or can be easily prepared by known procedures. For example, the acid starting material for benzoic acid chloride (IV: A is H; B, D is isopropyl; C is OMe) can be prepared using a modification of the method of Schuster, et al., J. Org. Chem. 1988, 53, 5819. Thus commercially available 2, 6-diisopropyl phenol is brominated in the 4-position (bromine/acetic acid), methylated (iodomethane/potassium carbonate/DMF), reacted with n-butyl lithium to effect lithium halogen exchange and the resultant organolithium species is reacted with carbon dioxide to provide 3, 5-diisopropyl, 4-methoxy benzoic acid. 
Further derivatives of the compounds of formula (I) in Scheme 2 can be prepared by the following methods. The phenol of formula (Ib: B, D, X is H; C is OH; E is S or O) (Scheme 2) can be conveniently iodinated to the diiodophenol of formula (Ib: B, D is I; X is H; C is OH; E is S or O) using at least two molar equivalents of iodine in -the presence of two or more molar equivalents of an alkali metal hydroxide such as NaOH in a alcohol solvent such as methanol at xe2x88x9220xc2x0 C. to room temperature. Similarly the monoiodophenol (Ib: B is I; X, D is H; C is OH; E is S or O) can be prepared from the phenol of formula (Ib: B, D, X is H; C is OH; E is S or O) (Scheme 2) using one to 1.5 molar equivalents of iodine in the presence of at least one equivalent of an alkali metal hydroxide such as NaOH in a alcohol solvent such as methanol at xe2x88x9220xc2x0 C. to room temperature. Either the monoiodophenol (Ib: B is I; X, D is H; C is OH; E is S or O) or the diiodophenol (Ib: B, D is I; X is H; C is OH; E is S or O) can be converted to the respective methyl ether derivatives of formula (Ib: B is I; X, D is H; C is OMe; E is S or O) or (Ib: B, D is I; X is H; C is OMe; E is S or O) by reacting the phenol moiety with a suitable methylating agent such as one or more molar equivalents of methyl iodide or dimethylsulfate employing a base such an alkali methyl carbonate or hydroxide such as potassium carbonate or sodium hydroxide in a suitable solvent such as THF, DMF or DMSO. The reaction is generally performed at temperatures ranging from 0xc2x0 C. to 60xc2x0 C.
The monoiodo methylether derivative of formula (Ib: B is I; X, D is H; C is OMe; E is S or O) or the diiodo methylether of formula (Ib: B, D is I; X is H; C is OMe; E is S or O) can be reacted with one or more molar equivalents of copper (I) cyanide for the monoiodo analog or two or more molar equivalents of copper (I) cyanide for the diiodo derivative to produce the monocyanomethyl ether of formula (Ib: B is CN; X, D is H; C is OMe; E is S or O) or the dicyanomethyl ether of formula (Ib: B, D is CN; X is H; C is OMe; E is S or O). The cyanation reaction is generally performed at temperatures ranging from 100xc2x0 C. to 250xc2x0 C. employing polar aprotic solvents such as DMF, 1-methyl-2-pyrrolidinone or HMPA. Quinoline or pyridine can also be used. The mono or dicyano methoxy analogs of formula (Ib: B is CN; D is H or CN; X is H; C is OMe; E is S or O); can be converted to the corresponding mono or dicyano phenol analogs of formula (Ic: B is CN; D is H or CN; X is H; E is S or O) (Scheme 2) using standard demethylation procedures including one or more molar equivalents of boron tribromide or boron trichloride in dichloromethane at xe2x88x9278xc2x0 C. to room temperature; excess neat pyridinium hydrochloride at 190 to 280xc2x0 C.; hydrobromic acid in acetic acid at 0xc2x0 C. to 50xc2x0 C.; excess trimethylsilylbromide or trimethylsilyliodide in dichloromethane, carbon tetrachloride or acetonitrile at xe2x88x9278xc2x0 C. to 50xc2x0 C.; lithium iodide in pyridine or quinoline at temperatures from 100xc2x0 to 250xc2x0 C. and one or more molar equivalents of ethyl, methyl or isopropyl mercaptan in the presence of one or more molar equivalents of a Lewis acid such as aluminum trichloride or boron trifluoride in a solvent such as dichloromethane at temperatures ranging from xe2x88x9278xc2x0 C. to 50xc2x0 C.
The monoiodo methylether derivative of formula (Ib: B is I; X, D is H; C is OMe; E is S or O) or the diiodo methylether of formula (Ib: B, D is I; X is H; C is OMe; E is S or O) (Scheme 2) can be reacted with one or more molar equivalents of copper (I) bromide for the monoiodo analog or two or more molar equivalents of copper (I) bromide for the diiodo derivative to produce the monobromo methyl ether of formula (Ib: B is Br; X, D is H; C is OMe; E is S or O) or the dibromo-methyl ether of formula (Ib: B, D is Br; X is H; C is OMe; E is S or O). The bromine/idodine exchange reaction is generally performed at temperatures ranging from 100xc2x0 C. to 250xc2x0 C. employing polar aprotic solvents such as DMF, 1-methyl-2-pyrrolidinone or HMPA. Quinoline or pyridine can also be used. The mono or dibromo methoxy analogs of formula (Ib: B is Br; D is H or Br X is H; C is OMe; E is S or O) can be converted to the corresponding mono or dibromo phenol analogs of formula (Ic: B is Br; D is H or Br; X is H; E is S or O) (Scheme 2) using standard demethylation procedures including one or more molar equivalents of boron tribromide or boron trichloride in dichloromethane at xe2x88x9278xc2x0 C. to room temperature; excess neat pyridinium hydrochloride at 190 to 280xc2x0 C.; hydrobromic acid in acetic acid at 0xc2x0 C. to 50xc2x0 C.; excess trimethylsilylbromide or trimethylsilyliodide in dichloromethane, carbon tetrachloride or acetonitrile at xe2x88x9278xc2x0 C. to 50xc2x0 C.; lithium iodide in pyridine or quinoline at temperatures from 100xc2x0 to 250xc2x0 C. and one or more molar equivalents of ethyl, methyl or isopropyl mercaptan in the presence of one or more molar equivalents of a Lewis acid such as aluminum trichloride or boron trifluoride in a solvent such as dichloromethane at temperatures ranging from xe2x88x9278xc2x0 C. to 50xc2x0 C. 
Further derivatives of the compounds of formula (I) in Scheme 3 can be prepared by the following methods. The compounds of formula (Id: B, C, D is H or OH; with the B. C, D combination having at least one OH group; E is S or O) (Scheme 3) can be acylated on the phenolic oxygen using one or more molar equivalents of suitable acylating agent to provide the compounds of formula (Id: B, C, D is H or OCOR; with the B, C, D combination having at least one OCOR group; R is alkyl of 1-6 carbon atoms, aryl; E is S or O). The acylating agent is generally alkyl of 1-6 carbon atoms or aryl carboxylic acid anhydride or alkyl of 1-6 carbon atoms or aryl carboxylic acid chloride. The reaction is run under standard conditions, for example the use of pyridine as solvent with or without a co-solvent such as dichloromethane at 0xc2x0 C. to room temperature. The acylated phenols of formula (Id: B, C, D is H or OCOR; with the B, C, D combination having at least one OCOR group; R is alkyl of 1-6 carbon atoms, aryl; E is S or O) can then be brominated in the 9-position of the naphtho[2,3-b]thiophene or the naphtho[2,3-b]furan ring to form the acylated bromophenols of formula (Ie: B, C, D is H or OCOR; with the B, C, D combination having at least one OCOR group; R is alkyl of 1-6 carbon atoms, aryl; X is Br; E is S or O) (Scheme 3). This bromination reaction is generally done using 1 to 1.3 molar equivalents of molecular bromine in the dark with a catalytic amount of iron (III) chloride in an inert solvent such as dichloromethane or carbon tetrachloride at temperatures ranging from xe2x88x9278xc2x0 C. to room temperature.
Using a similar bromination reaction, the phenols of formula (Id: B, D is alkyl of 1-6 carbon atoms, C is OH; E is S or O) can then be brominated in the 9-position of the naphtho[2,3-b]thiophene hene or the naphtho[2,3-b]furan ring to form the bromophenols of formula (Ie: B, D is alkyl of 1-6 carbon atoms, C is OH; X is Br; E is S or O) (Scheme 3). This bromination reaction is generally done using 1 to 1.3 molar equivalents of molecular bromine in the dark with a catalytic amount of iron (III) chloride in an inert solvent such as dichloromethane or carbon tetrachloride at temperatures ranging from xe2x88x9278xc2x0 C. to room temperature.
The acyl group can then be removed from the acylated bromophenols of formula (Ie: B, C, D is H or OCOR; with the B, C, D combination having at least one OCOR group; R is alkyl of 1-6 carbon atoms, aryl; X is Br; E is S or O) to provide the bromophenols of formula (Ie: B, C, D is H or OH; with the B, C, D combination having at least one OH group; X is Br; E is S or O) (Scheme 3) using standard conditions. These conditions include aqueous base in which one or more molar equivalents of alkali metal hydroxide such as sodium hydroxide is used in water with a co-solvent such as THF, dioxane or a 1-6 carbon alcohol such as methanol or mixtures of THF and a 1-6 carbon atom alcohol at temperatures ranging from 0xc2x0 C. to 40xc2x0 C. Acid conditions may also be employed in which the compound is reacted with one or more molar equivalents of a mineral acid such as HCl or sulfuric acid in water with or without a co-solvent such as THF at temperatures ranging from room temperature to 80xc2x0 C.
The acylated phenols of formula (Id: B, C, D is H or OCOR; with the B, C, D combination having at least one OCOR group; R is alkyl of 1-6 carbon atoms, aryl; E is S or O) can be nitrated to provide the nitro compounds of formula (Ie: B, C, D is H or OCOR; with the B, C,,D combination having at least one OCOR group; R is alkyl of 1-6 carbon atoms, aryl; X is NO2; E is S or O) (Scheme 3). Dilute nitric acid at temperatures ranging from 0xc2x0 C. to room temperature is suitable to effect this transformation. The nitro compounds of formula (Ie: B, C, D is H or OCOR; C, D cannot both be H; R is alkyl fo 1-6 carbon atoms, aryl; X is NO2; E is S or O) can be further reduced to the primary amine of formula (1e: B, C, D is H or OCOR; with the B, C, D combination having at least one OCOR group; R is alkyl fo 1-6 carbon atoms, aryl; X is NH2; E is S or O) using a suitable reducing agent such as catalytic hydrogenation with a palladium or platinum catalyst, tin dichloride in aqueous HCl or in ethyl acetate. The acyl group of the compounds of formula (Ie: B, C, D is H or OCOR; with the B, C, D combination having at least one OCOR group; R is alkyl of 1-6 carbon atoms, aryl; X is NO2 or NH2; E is S or O) can be removed using standard conditions.
The acylated bromophenols of formula (Ie: B, C, D is H or OCOR; with the B, C, D combination having at least one OCOR group; R is alkyl of 1-6 carbon atoms, aryl; X is Br; E is S or O) (Scheme 3) can be converted to the acylated cyanophenols of formula (Ie: B, C, D is H or OCOR; with the B, C, D combination having at least one OCOR group; R is alkyl of 1-6 carbon atoms, aryl; X is CN; E is S or O) by reaction with one or more molar equivalents of copper (I) cyanide. The cyanation reaction is generally performed at temperatures ranging from 100xc2x0 C. to 250xc2x0 C. employing polar aprotic solvents such as DMF, 1-methyl-2-pyrrolidinone or HMPA. Quinoline or pyridine can also be used. Often the acyl group of (Ie: B, C, D is H or OCOR; with the B, C, D combination having at least one OCOR group; R is alkyl of 1-6 carbon atoms, aryl; X is CN; E is S or O) is liberated under the cyanation reaction conditions to afford the cyanophenols of formula (Ie: B, C, D is H or OH; with the B, C, D combination having at least one OH group; X is CN; E is S or O). This liberation of the acyl group to afford the cyanophenols of formula (Ie: B, C, D is H or OH; with the B, C, D combination having at least one OH group; X is CN; E is S or O) can be effected most readily by addition of one or more molar equivalents of alkali metal hydroxide in water to the reaction mixture containing (Ie: B, C, D is H or OCOR; with the B, C, D combination having at least one OCOR group; R is alkyl of 1-6 carbon atoms, aryl; X is CN; E is S or O) prior to workup. The acyl group can also be removed from the isolated acylated cyanophenols of formula (Ie: B, C, D is H or OCOR; with the B, C, D combination having at least one OCOR group; R is alkyl of 1-6 carbon atoms, aryl; X is CN; E is S or O) to provide the cyanophenols of formula (Ie: B, C, D is H or OH; with the B, C, D combination having at least one OH group; R is alkyl of 1-6 carbon atoms, aryl; X is CN; E is S or O) using standard conditions. These conditions include aqueous base in which one or more molar equivalents of alkali metal hydroxide such as sodium hydroxide is used in water with a co-solvent such as THF, dioxane or a lower alcohol such as methanol or mixtures of THF and a lower alcohol at temperatures ranging from 0xc2x0 C. to 40xc2x0 C. Acid conditions may also be employed in which the compound is reacted with one or more molar equivalents of a mineral acid such as HCl or sulfuric acid in water with or without a co-solvent such as THF at temperatures ranging from room temperature to 80xc2x0 C.
The compounds of formula (Id: B, C, D is H or OH; with the B, C, D combination having at least one OH group; E is S or O) (Scheme 3) can be sulfonylated on the phenolic oxygen using one or more molar equivalents of suitable sulfonylating agent to provide the sulfonic acid esters of formula (Id: B, C, D is H or OSO2R; with the B, C, D combination having at least one OSO2R group; R is alkyl of 1-6 carbon atoms, aryl; E is S or O). The sulfonylating agent is generally a alkyl of 1-6 carbon atoms or aryl sulfonic acid anhydride or a alkyl of 1-6 carbon atoms or aryl sulfonic acid chloride. The reaction is run under standard conditions such as using pyridine as solvent with or without a co-solvent such as dichloromethane at 0xc2x0 C. to room temperature.
The sulfonic acid esters of formula (Id: B, C, D is H or OSO2R; with the B, C, D combination having at least one OSO2R group; R is alkyl of 1-6 carbon atoms, aryl; E is S or O) can be treated with iodinating reagents to effect iodination at the 9-position of the naphtho[2,3-d]thiophene or the naphtho[2,3-d]furan ring to afford the iodo sulfonic acid esters of formula (Ie: B, C, D is H or OSO2R; with the B, C, D combination having at least one OSO2R group; R is alkyl of 1-6 carbon atoms, aryl; X is I; E is S or O). A suitable iodinating reagent includes a mixture of 0.7 or more molar equivalents of molecular iodine and 0.25 or more molar equivalents of iodic acid in a mixture of THF and 80% aqueous acetic acid with a small amount of concentrated sulfuric acid at temperatures ranging from room temperature to 80xc2x0 C. The sulfonic ester group can then be removed from the iodo-sulfonic acid esters of formula (Ie: B, C, D is H or OSO2R; with the B, C, D combination having at least one OSO2R group; R is alkyl of 1-6 carbon atoms, aryl; X is I; E is S or O) to provide the iodophenols of formula (Ie: B, C, D is H or OH; with the B, C, D combination having at least one OH group; X is I; E is S or O) (Scheme 3) using standard conditions. These conditions include aqueous base in which one or more molar equivalents of alkali metal hydroxide such as sodium hydroxide is used in water with a co-solvent such as THF, dioxane or a lower alcohol such as methanol or mixtures of THF and a lower alcohol at temperatures ranging from room temperature to 110xc2x0 C. 
The iodo sulfonic acid esters of formula (If: C, D is H or OSO2R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl) ; E is S or O are a convenient starting point for further derivatives of the compounds of formula (I) as shown in Scheme 4 and the methods below. The compounds (If: C, D is H or OSO R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; E is S or O) can be reacted with a reagent that catalyzes the exchange of the iodine atom in (If) with a lower perfluoroalkyl group to afford the compound of formula (Ig: C, D is H or OSO2R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; X is lower perfluoroalkyl; E is S or O) (Scheme 4). The reagent and conditions to effect this exchange include reacting (If) under anhydrous conditions with one to ten molar equivalents of a sodium perfluorocarboxylate (RCO2Na: R is perfluoroalkyl) and one to five molar equivalents of copper (I) iodide in a high boiling inert solvent such as DMF, DMA or 1-methyl-2-pyrrolidinone at temperatures ranging from 140xc2x0 C. to 200xc2x0 C. Alternatively, the compound of formula (Ig: C, D is H or OSO2R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; X is lower perfluoroalkyl; E is S or O) can be prepared from the compound of formula (If: C, D is H or OSO2R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; E is S or O) by reacting the former with one to ten molar molar equivalents of a perfluoroalkyl iodide and one to five molar molar equivalents of activated Cu0 in a high boiling inert solvent such as DMF, DMA or 1-methyl-2-pyrrolidinone at temperatures ranging from 140xc2x0 C. to 200xc2x0 C. Still, alternatively, the compound of formula (If: C, D is H or OSO2R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; E is S or O) can be reacted with 0.5 to two molar equivalents of bis(trifluoromethyl)mercury and two to four molar equivalents of activated Cu0 in a high boiling inert solvent such as DMF, DMA or 1-methyl-2-pyrrolidinone at temperatures ranging from 140xc2x0 C. to 200xc2x0 C. to produce the compound of (Ig: C, D is H or OSO2R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; X is CF3; E is S or O).
9-alkyl derivatives of the compound of formula (Ig: C, D is H or OSO2R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; X is alkyl of 1-6 carbon atoms; E is S or O) (Scheme 4) can be prepared by reaction of (If: C, D is H or OSO2R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; E is S or O) with three or more molar equivalents of lower tetra-alkyltin in the presence of a palladium catalyst such as 1 to 10 mole % of bis(triphenylphosphine)palladium II chloride in a suitable solvent such as DMF, DMA or 1-methyl-2-pyrrolidinone at temperatures ranging from 140xc2x0 C. to 200xc2x0 C.
The sulfonic ester group can then be removed from the sulfonic acid esters of formula (Ig: C, D is H or OSO2R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; X is alkyl of 1-6 carbon atoms or lower perfluoroalkyl; E is S or O) to provide the phenols of formula (Ig: C, D is H or OH; C, D cannot both be H; X is alkyl of 1-6 carbon atoms or lower perfluoroalkyl; E is S or O) using standard conditions. These conditions include aqueous base in which one or more molar equivalents of alkali metal hydroxide such as sodium hydroxide is used in water with a co-solvent such as HF, dioxane or a lower alcohol such as methanol or mixtures of THF and a lower alcohol at temperatures ranging from room temperature to 110xc2x0 C.
9-Alkoxy derivatives of the compound of formula (Ig: C, D is H, OH; C, D cannot both be H; X is alkoxy of 1-6 carbon atoms; E is S or O) can be prepared by reaction of (If: C, D is H or OSO2R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; E is S or O) with three or more molar equivalents of lower alkali metal alkoxide such as sodium methoxide in the presence of a copper (I) or copper (II) catalyst such as 1 to 10 mole % copper (II) chloride in a suitable solvent such as DMF, DMA or 1-methyl-2-pyrrolidinone at temperatures ranging from 80xc2x0 C. to 180xc2x0 C. Under the reaction conditions, the sulfonic acid group of formula (If: C, D is H or OSO2R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; E is S or O) is removed.
9-Sulfanyl derivatives of the compound of formula (Ig: C, D is H or OH; C, D cannot both be H; X is alkyl of 1-6 carbon atomssulfanyl, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; E is S or O) can be prepared by reaction of formula (If: C, D is H or OSO2R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; E is S or O) with one or more molar equivalents of the appropriate alkyl of 1-6 carbon atomsthiol, arylthiol, thiopyridine or 2-N,N-dimethylaminoethyl-mercaptan, one or more molar equivalents of an alkali metal hydroxide such as sodium hydroxide, one or more molar equivalents of a copper (I) or copper (II) catalyst such as copper (I) oxide in a suitable solvent such as DMF, DMA or 1-methyl-2-pyrrolidinone at temperatures ranging from 100xc2x0 C. to 180xc2x0 C. Under the reaction conditions, the sulfonic acid group of formula (If: C, D is H or OSO2R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; E is S or O) is removed. 
Further derivatives of the compounds of formula (I) in Scheme 5 can be prepared by the following methods. The phenols of formula (Ih: A is H or OH; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; E is S or O) can be brominated in two positions to afford the dibromphenols of formula (Ii: A is H or OH; B, D is Br; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; E is S or O) using at least 2 molar equivalents of molecular bromine in an appropriate solvent such as acetic acid. One to fifty molar equivalents of a salt of acetic acid such as potassium or sodium acetate can also be used as a co-reagent in this reaction although it is not absolutely required.
The phenols of formula (Ih: A is H; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; E is S or O) can be mononitrated to the phenols of formula (Ii: A is H; B is NO2; D is H; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; E is S or O) most conveniently using iron (III) trinitrate in a lower alcohol solvent.
The nitro compounds of formula (Ii: A is H; B is NO2; D is H; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; E is S or O) can be reduced to the amino compounds of formula (Ii: A is H; B is NH2; D is H; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, amino, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; E is S or O) most readily using tin dichloride in ethylacetate at 40 to 100xc2x0 C. or with hydrazine and Montmorillinite clay in ethanol at 40 to 100xc2x0 C.
The nitro compounds of formula (Ii: A is H; B is NO2; D is H; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; E is S or O) can also be brominated to the compounds of formula (Ii: A is H; B is NO2; D is Br; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; E is S or O) using at least 2 molar equivalents of molecular bromine in an appropriate solvent such as acetic acid. One to fifty molar equivalents of a salt of acetic acid such as potassium or sodium acetate can also be used as a co-reagent in this reaction although it is not absolutely required. The bromo nitro compounds of formula (Ii: A is H; B is NO2; D is Br; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; E is S or O) can be reduced to the bromo amino compounds of formula (Ii: A is H; B is NH,; D is Br; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, amino, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; E is S or O) most readily using tin dichloride in ethylacetate at 40 to 100xc2x0 C. or with hydrazine and Montmorillinite clay in ethanol at 40 to 100xc2x0 C.
The amino compounds of formula (Ii: A is H; B is NH2; D is H or Br; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, amino, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; E is S or O) can be acylated with one or more equivalents of a suitable acylating agent of formula (LG)COR1a or (LG)CO2R1a (wherein LG is a leaving group such as Cl for an acyl halide or chloroformate or OCOR1a or OCO2R1a for an anhydride or mixed anyhdride, etc.; R1a is alkyl of 1-6 carbon atoms, aralkyl and aryl) to produce the compounds of formula (Ii: A is H; B is NHCOR1a or NHCO2R1a; D is H or Br; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, amino, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; E is S or O; R1a is . R1a is alkyl of 1-6 carbon atoms aralkyl and aryl). These acylations can be performed in the presence of one or more equivlents of a suitable base such as an alkali metal hydroxide, carbonate or bicarbonate or an organic amine base such as triethylamine or pyridine and with or without a suitable solvent such a chloroform, dichloromethane, THF, dioxane and water or mixtures of these solvents and with or without the presence of a catalyst such as 4-N, N-dimethylpyridine.
The dibromo-bisphenols of formula (Ii: A is OH; B, D is Br; X is H; E is S or O) can be further brominated in the 9-position of the naphtho[2,3-b]thiophene or the naphtho[2,3-b]furan ring to form the bisphenols of formula (Ii: A is OH; B, D, X is Br; E is S or O). This bromination reaction is generally done using 1 to 1.3 molar equivalents of molecular bromine in the dark with a catalytic amount of iron (III) chloride in an inert solvent such as dichloromethane or carbon tetrachloride at temperatures ranging from xe2x88x9278xc2x0 C. to room temperature. 
Further derivatives of the compounds of formula (I) in Scheme 6 can be prepared by the following methods. The phenols of formula (Ij: C is H; D is OH; X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; E is S or O) can be monobrominated to provide the provide the bromophenols of formula (Ik: A, B is H; C is Br; D is OH; X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; E is S or O) using at least 1 molar equivalent of molecular bromine in an appropriate solvent such as acetic acid or dibrominated to provide the bromophenols of formula (Ik: B is H; A, C is Br; D is OH; X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; E is S or O) using at least 2 molar equivalents of molecular bromine in an appropriate solvent such as acetic acid. Similarly, the bisphenols of formula (Ij: C, D is OH; X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; E is S or O) can be monobrominated to provide a mixture of the bromobisphenols of formula (Ik: A is H; B is Br; C, D is OH; X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; E is S or O) and (Ik: A is Br; B is H; C, D is OH; X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; E is S or O) using at least 1 molar equivalents of molecular bromine in an appropriate solvent such as acetic acid. This mixture can be separated into pure monobromo products by conventional means. 
Further derivatives of the compounds of formula (I) in Scheme 7 can be prepared by the following methods. The phenols of formula (Il: B is H; A, C is H or Br; D is OH; X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; E is S or O) can be alkylated with one or more molar equivalents of an alkyl haloacetate of formula (X2CHR6aCO2R6 where X2 is Cl, Br or I and R6 is alkyl of 1-6 carbon atoms, R6a is H) and with one or more molar equivalents of an alkali metal carbonate such as potassium carbonate in a polar aprotic solvent such as DMF to afford the alkylated product of formula (Im: B is H; A, C is H or Br; X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; R6 is alkyl of 1-6 carbon atoms, R6a is H; E is S or O).
Alternatively the bisphenols of formula (Il: A, B is H or Br; C, D is OH; X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; E is S or O) can be diaklylated with two or more molar equivalents of an alkyl haloacetate of formula (X2CHR6aCO2R6 where X2 is Cl, Br or I and R6 is alkyl of 1-6 carbon atoms, R6a is H) and with two or more molar equivalents of an alkali metal carbonate such as potassium carbonate in a polar aprotic solvent such as DMF to afford the dialkylated esters of formula (Im: A, B is H or Br; C is OCH2CO2R6; X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; R6 is alkyl of 1-6 carbon atoms, R6a is H; E is S or O).
Still alternatively, the phenols of formula (Il: B is H or halogen; A is H or halogen; C is H, Br or alkoxy of 1-6 carbon atoms; D is OH; X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; E is S or O) can be reacted with a 2-hydroxy carboxylic acid ester of formula CH(OH)(R6a)CO2R6 (R6, R6a is alkyl of 1-6 carbon atoms, aralkyl, aryl) to afford the esters of formula (Im: B is H or halogen; A is H or halogen; C is H, Br or alkoxy of 1-6 carbon atoms; X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; R6, R6a is alkyl of 1-6 carbon atoms, aralkyl, aryl; E is S or O) under the conditions of the Mitsunobu Reactions (for a review see Oyo Mitsunobu Synthesis. 1981, 1-27). The other co-reagents necessary to effect the Mitsunobu Reaction include one or more molar equivalents of a alkyl of 1-6 carbon atoms azodicarboxylate diester such as diethyl azodicarboxylate or diisopropyl azodicarboxylate and one or more molar equivalents of triarylphosphine such as triphenylphosphine in a suitable solvent such as diethyl ether, THF, benzene or toluene at temperatures ranging from xe2x88x9220xc2x0 C. to 120xc2x0 C.
The monoesters of formula (Im: A, B is H or halogen; C is H, Br or alkoxy of 1-6 carbon atoms; X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; R6, R6a is alkyl of 1-6 carbon atoms, aralkyl, aryl; E is S or O) as well as the diesters of formula (Im: A, B is H or Br; C is OCH2CO2R6, X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; R6 is alkyl of 1-6 carbon atoms, R6a is H; E is S or O) can be transformed into their carboxylic acid analogs using standard conditions to afford the moncarboxylic acids of formula (Im: A, B is H or halogen; C is H, Br or alkoxy of 1-6 carbon atoms; X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; R6 is H; R6, is alkyl of 1-6 carbon atoms, aralkyl, aryl; E is S or O) and the dicarboxylic acids of formula (Im: A, B is H or Br; C is OCH2CO2H, X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; R6, R6a is H; E is S or O). The conditions to effect these transformations include aqueous base in which one or more molar equivalents of alkali metal hydroxide such as sodium hydroxide is used in water with a co-solvent such as THF, dioxane or a lower alcohol such as methanol or mixtures of THF and a lower alcohol at temperatures ranging from 0xc2x0 C. to 40xc2x0 C. 
Further derivatives of the compounds of formula (I) in Scheme 8 can be prepared by the following methods. The acetates of formula (In: X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; Y is H; E is S or O) can be reacted with a halogenating agent, specifically one that causes benzylic type bromination or chlorination such as one or more molar equivalents of N-bromosuccinimide, N-chlorosuccinimide or sulfuryl chloride to provide the halo acetates of formula (In: X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; Y is Cl, Br; E is S or O). This reaction is conveniently done in a suitable solvent such as dichloromethane or carbontetrachloride at temperatures ranging from 0xc2x0 C. to room temperature.
The halo acetates of formula (In: X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; Y is Cl, Br; E is S or O) can be reacted with one or more equivalents of nucleophiles such as alkoxides (MOR1), sulfides (MSR1) or amines (NHR1R2) (wherein M is a alkali metal such as Na, Li or K; R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl) in a suitable solvent such as THF, DMF or dichloromethane to provide the compounds of formula (In: X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; Y is OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O). During reaction of the compounds of formula (In: X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; Y is Cl, Br; E is S or O) with nucleophiles there can be concomitent loss of the acetyl group to afford the compounds of formula (Io: B, D is H; X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; Y is OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O).
The compounds of formula (In: X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; Y is OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) can be deacylated to produce the compounds of formula (Io: B, D is H; X-is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; Y is Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O). The deacylation conditions include aqueous base in which one or more molar equivalents of alkali metal hydroxide such as sodium hydroxide is used in water with a co-solvent such as THF, dioxane or a lower alcohol such as methanol or mixtures of THF and a lower alcohol at temperatures ranging from 0xc2x0 C. to 40xc2x0 C. Acid conditions may also be employed in which the compound is reacted with one or more molar equivalents of a mineral acid such as HCl or sulfuric acid in water with or without a co-solvent such as THF at temperatures ranging from room temperature to 80xc2x0 C.
The compounds of formula (Io: B, D is H; X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; Y is Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) can be brominated in two positions to afford the dibromphenols of formula (Io: B, D is Br; X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; Y is Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) using at least 2 molar equivalents of molecular bromine in an appropriate solvent such as acetic acid. One to fifty molar equivalents of a salt of acetic acid such as potassium or sodium acetate can also be used as a co-reagent in this reaction although it is not absolutely required. 
Further derivatives of the compounds of formula (I) in Scheme 9 can be prepared by the following methods. The phenols of formula (Ip: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) can be alkylated with one or more molar equivalents of an alkyl haloacetate of formula (X2CH2CO2R6 where X2 is Cl, Br or I and R6 is alkyl of 1-6 carbon atoms) and with one or more molar equivalents of an alkali metal carbonate such as potassium carbonate in a polar aprotic solvent such as DMF to afford the alkylated product of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms., aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W is CO2R6; R5is H; R6 is alkyl of 1-6 carbon atoms; E is S or O).
The phenols of formula (Ip: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) can be reacted with a 2-hydroxy carboxylic acid ester of formula CH(OH)(R5)CO2R6 (R5 is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, CH2(1H-imidazol-4-yl), CH2(3-1H-indolyl), CH2CH2(1,3-dioxo-1,3-dihydro-isoindol-2-yl), CH2CH2(1-oxo-1,3-dihydro-isoindol-2-yl), CH2(3-pyridyl), CH2CO2R6, R6 is alkyl of 1-6 carbon atoms) to afford the esters of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W is CO2R6; R5 is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, CH2(1H-imidazol-4-yl), CH2(3- 1H-indolyl), CH2CH2(1,3-dioxo-1,3-dihydro-isoindol-2-yl), CH2CH2(1-oxo-1,3-dihydro-isoindol-2-yl), CH2(3-pyridyl), CH2CO2R6, R6 is alkyl of 1-6 carbon atoms; E is S or O) under the conditions of the Mitsunobu Reactions (for a review see Oyo Mitsunobu Synthesis. 1981, 1-27). The other co-reagents necessary to effect the Mitsunobu Reaction include one or more molar equivalents of a alkyl of 1-6 carbon atoms azodicarboxylate diester such as diethyl azodicarboxylate or diisopropyl azodicarboxylate and one or more molar equivalents of triarylphosphine such as triphenylphosphine in a suitable solvent such as diethyl ether, THF, benzene or toluene at temperatures ranging from xe2x88x9220xc2x0 C. to 120xc2x0 C.
The 2-hydroxy carboxylic acid ester of formula CH(OH)(R5)CO2R6 (R5 is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, CH2(1H-imidazol-4-yl), CH2(3-1H-indolyl), CH2CH2(1,3-dioxo-1,3-dihydro-isoindol-2-yl), CH2CH2(1-oxo-1,3-dihydro-isoindol-2-yl), CH2(3-pyridyl), CH2CO2R6, R6 is alkyl of 1-6 carbon atoms) are commercially available or can be prepared from commercially available carboxylic acid precursors under standard esterification conditions. (S)-(+)-2-Hydroxy-1-oxo-3-dihydro-2-isoindolinebutyric acid, methyl ester can be prepared from (S)-(+)-2-hydroxy-1,3-dioxo-2-isoindolinebutyric acid, methyl ester via sequential treatment with 1) sodium borohydride in THF-water; 2) trifluoroacetic acid/chloroform; 3) triethylsilane/trifluoroacetic acid and 4) aqueous sodium bicarbonate. 3-(Pyridin-3-yl)-phenyllactic acid, ethyl ester can be prepared according to the two step procedure of B. A. Lefker, W. A. Hada, P. J. McGarry Tetrahedron Lett. 1994, 35, 5205-5208, from commericially available 3-pyridinecarboxaldehyde and ethyl chloroacetate.
The esters of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W is CO2tBu; R5 is H; E is S or O) can be treated with one or more molar equivalents of a strong base such as lithium diisopropyl amide in a suitable solvent such as THF at temperatures ranging from xe2x88x9278xc2x0 C. to room temperature. This procedure produces an anion alpha to the ester carbonyl. The resultant anion is treated with one or more molar equivalents of an alkyl halide of formula X2R5 (where X2 is halogen; R5 is alkyl and aralkyl) and warmed to room temperature to produce the alkylated ester of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W is CO2tBu; R5 is alkyl and aralkyl; E is S or O).
The esters of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W is CO2R6; R5 is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, CH2(1H-imidazol-4-yl), CH2(3-1H-indolyl), CH2CH2(1,3-dioxo-1,3-dihydro-isoindol-2-yl), CH2CH2(1 -oxo-1,3-dihydro-isoindol-2-yl), CH2(3-pyridyl), CH2CO2R6, R6 is alkyl of 1-6 carbon atoms; E is S or O) can be transformed into their carboxylic acid analogs using standard conditions to afford the carboxylic acids of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W is CO2H; R5 is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, CH2(1H-imidazol-4-yl), CH2(3-1H-indolyl), CH2CH2(1,3-dioxo-1,3-dihydro-isoindol-2-yl), CH2CH2(1-oxo-1,3-dihydro-isoindol-2-yl), CH2(3-pyridyl), CH2CO2H; E is S or O). The conditions to effect these transformations include aqueous base in which one or more molar equivalents of alkali metal hydroxide such as sodium hydroxide is used in water with a co-solvent such as THF, dioxane or a lower alcohol such as methanol or mixtures of THF and a lower alcohol at temperatures ranging from 0xc2x0 C. to 40xc2x0 C. Alternatively, acid conditions may also be employed in which the aboved mentioned carboxylic acid ester of formula (Iq) is reacted with one or more molar equivalents of a mineral acid such as HCl or sulfuric acid in water with or without a co-solvent such as THF at temperatures ranging from room temperature to 80xc2x0 C. Still alternatively, many other conditions may be employed to effect the above mentioned ester to acid transformation leading to (Iq). These include reacting the carboxylic acid ester of formula (Iq) with one or more molar equivalents of boron tribromide or boron trichloride in dichloromethane at xe2x88x9278xc2x0 C. to room temperature; one or more molar equivalents hydrobromic acid in acetic acid at 0xc2x0 C. to 50xc2x0 C.; one or more molar equivalents trimethylsilylbromide or trimethylsilyliodide in dichloromethane, carbon tetrachloride or acetonitrile at xe2x88x9278xc2x0 C. to 50xc2x0 C.; one or more molar equivalents lithium iodide in pyridine or quinoline at temperatures from 100xc2x0 to 250xc2x0 C.
The phenols of formula (Ip: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) can be alkylated with one or more molar equivalents of diethyl trifluoromethylsulfonyloxymethylphosphanate (D. P. Phillion and S. S. Andrew Tet. Lett. 1986, 1477-1480) and with one or more molar equivalents of an alkali metal hydride such as sodium hydride in a suitable solvent such as THF or DMF to afford the diethylphosphonate product of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W is PO3Et2; R5 is H; R6 is alkyl of 1-6 carbon atoms; E is S or O).
The phenols of formula (Ip: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) can be reacted with a 2-hydroxy phosphonic acid diester of formula CH(OH)(R5)PO3(R6)2, (R5 is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, R6 is alkyl of 1-6 carbon atoms) to afford the phosphonic acid diesters of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W is PO3(R6)2; R5 is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, R6 is alkyl of 1-6 carbon atoms; E is S or O) under the conditions of the Mitsunobu Reactions (for a review see Oyo Mitsunobu Synthesis 1981, 1-27). The other co-reagents necessary to effect the Mitsunobu Reaction include one or more molar equivalents of a alkyl of 1-6 carbon atoms azodicarboxylate diester such as diethyl azodicarboxylate or diisopropyl azodicarboxylate and one or more molar equivalents of triarylphosphine such as triphenylphosphine in a suitable solvent such as diethyl ether, THF, benzene or toluene at temperatures ranging from xe2x88x9220xc2x0 C. to 120xc2x0 C.
The 2-hydroxy phosphonic acid diester of formula CH(OH)(R5)PO3R6 (R5 is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, R6 is alkyl of 1-6 carbon atoms) can be prepared by reacting a dialklylphosphonate of formula HP(O)(OR6)2 (R6 is alkyl of 1-6 carbon atoms) with an aldehyde of formula R5CHO (R5 is alkyl of 1-6 carbon atoms, aryl, aralkyl) under standard conditions.
The phosphonic acid diesters of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W is PO3(R6)2; R5 is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, R6 is alkyl of 1-6 carbon atoms; E is S or O) can be transformed into their phosphonic acid analogs using standard conditions to afford the phosphonic acids of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W is PO3H2; R5 is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, R6 is H, alkyl of 1-6 carbon atoms; E is S or O). The conditions that may also be employed in which the above mentioned phosphonic acid diester of formula (Iq) is reacted with two or more molar equivalents of a mineral acid such as HCl or sulfuric acid in water with or without a co-solvent such as THF at temperatures ranging from 40 to 100xc2x0 C. Still alternatively, many other conditions may be employed to effect the above mentioned diester to acid transformation leading to (Iq). These include reacting the phosphonic acid diester of formula (Iq) with two or more molar equivalents of boron tribromide or boron trichloride in dichloromethane at xe2x88x9278xc2x0 C. to room temperature; two or more molar equivalents hydrobromic acid in acetic acid at 0xc2x0 C. to 50xc2x0 C.; two or more molar equivalents trimethylsilylbromide or trimethylsilyliodide in dichloromethane, carbon tetrachloride or acetonitrile at xe2x88x9278xc2x0 C. to 50xc2x0 C.; two or more molar equivalents lithium iodide in pyridine or quinoline at temperatures from 60xc2x0 to 250xc2x0 C.
The esters of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl;,W is CO2R6; R5 is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, CH2(1H-imidazol-4-yl), CH2(3-1H-indolyl), CH2CH2(1-oxo-1,3-dihydro-isoindol-2-yl), CH2(3-pyridyl), R6is alkyl of 1-6 carbon atoms; E is S or O) can be transformed into their primary carboxylic acid amide analogs of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W is CONH2; R5 is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, CH2(1H-imidazol-4-yl), CH2(3-1H-indolyl), CH2CH2(1-oxo-1,3-dihydro-isoindol-2-yl), CH2(3-pyridyl) ; E is S or O) by reacting the ester starting material with ammonia gas dissolved in a lower alcohol solvent such as methanol or ethanol at temperatures ranging from 0xc2x0 C. to 100xc2x0 C.
Alternatively, the carboxylic acids of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W is CO2H; R5 is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, CH2(1H-imidazol-4-yl), CH2(3-1H-indolyl), CH2CH2(1,3-dioxo-1,3-dihydro-isoindol-2-yl), CH2CH2(1-oxo-1,3-dihydro-isoindol-2-yl), CH2(3-pyridyl) ; E is S or O) can be transformed into their carboxylic acid amide analogs of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W is CONH2, CONHOH, CONH(CH,)2CN; R5 is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, CH2(1H-imidazol-4-yl), CH2(3-1H-indolyl), CH2CH2(1,3-dioxo-1,3-dihydro-isoindol-2-yl), CH2CH2(1-oxo-1,3-dihydro-isoindol-2-yl), CH2(3-pyridyl); E is S or O). This transformation can be accomplished using standard methods to effect carboxylic acid to carboxylic acid amide transformations. These methods include converting the acid to an activated acid and reacting with one or more molar equivalents of the desired amine. Amines in this category include ammonia in the form of ammonium hydroxide, hydroxyl amine and 2-aminopropionitrile. Methods to activate the carboxylic acid include reacting said acid with one or more molar equivalents of oxalyl chloride or thionyl chloride to afford the carboxylic acid chloride in a suitable solvent such as dichloromethane, chloroform or diethyl ether. This reaction is often catalyzed by adding small amounts (0.01 to 0.1 molar equivalents) of dimethylformamide. Other methods to activate the carboxylic acid include reacting said acid with one or more molar equivalents dicyclohexylcarbodiimide with or without one or more molar equivalents of hydroxybenzotriazole in a suitable solvent such as dichloromethane or dimethylformamide at temperatures ranging from 0xc2x0 C. to 60xc2x0 C.
The phenols of formula (Ip: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) can be alkylated with one or more molar equivalents of a haloacetonitrile of formula (X2CH2CN where X2 is Cl, Br or I) and with one or more molar equivalents of an alkali metal carbonate such as potassium carbonate in a polar aprotic solvent such as DMF to afford the nitriles of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W is CN; R5is H; E is S or O).
Alternatively, the carboxylic acid amide analogs of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W is CONH2; R5 is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, CH2(1H-imidazol-4-yl), CH2(3-1H-indolyl), CH2CH2(1,3-dioxo-1,3-dihydro-isoindol-2-yl), CH2CH2(1-oxo-1,3-dihydro-isoindol-2-yl), CH2(3-pyridyl); E is S or O) can be converted to their nitrile analogs of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W is CONH2; R5 is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, CH2(1H-imidazol-4-yl), CH2(3-1H-indolyl), CH2CH2(1,3-dioxo-1,3-dihydro-isoindol-2-yl), CH2CH2(1-oxo-1,3-dihydro-isoindol-2-yl), CH2(3-pyridyl); E is S or O) by using reagents that dehydrate the primary carboxamide function to the nitrile function. One set of conditions to effect this transformation include reacting the said primary carboxylic acid amide with one or more molar equivalents of trifluoroacetic anhydride and two or more molar equivalents of pyridine in a suitable solvent such as dioxane at temperatures ranging from 60xc2x0 C. to 120xc2x0 C.
The nitriles analogs of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W is CN; R5 is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, CH2(1H-imidazol-4-yl), CH2(3-1H-indolyl), CH2CH2(1,3-dioxo-1,3-dihydro-isoindol-2-yl), CH2CH2(1-oxo-1,3-dihydro-isoindol-2-yl), CH2(3-pyridyl); E is S or O) can be converted to the tetrazoles of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W is 5-tetrazole; R5 is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, CH2(1H-imidazol-4-yl), CH2(3-1H-indolyl), CH2CH2(1,3-dioxo-1,3-dihydro-isoindol-2-yl), CH2CH2(1-oxo-1,3-dihydro-isoindol-2-yl), CH2(3-pyridyl); E is S or O) by reacting the nitrile function with one or more molar equivalents of trimethylaluminum and one or more molar equivalents of trimethylsilyl azide in a suitable solvent such as benzene or toluene at temperatures ranging from 60xc2x0 C. to 120xc2x0 C. Alternatively, the nitrile fuction can be reacted with one or more molar equivalents of ammonium azide in a suitable solvent such as dimethylformamide at temperatures ranging from 60xc2x0 C. to 160xc2x0 C. 
Further derivatives of the compounds of formula (I) in Scheme 10 can be prepared by the following methods. The phenols of formula (Ir: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) can be reacted with one or more molar equivalents of lithium (bis)trimethylsilylamide at temperautres ranging from xe2x88x9278xc2x0 C. to room temperature and the lithium salt can be further reacted with one or more molar equivalents of 5-bromothiazolidine-2, 4-dione (prepared according to the method of Zask, et al., J. Med Chem, 1990, 33, 1418-1423) using a suitable solvent such as THF under an inert atmosphere at temperautres ranging from xe2x88x9278xc2x0 C. to room temperature to provide the compounds of formula (Is: R4 is (R, S)-5-thiazolidine-2,4-dione; B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O).
Alternatively, the phenols of formula (Ir: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) can be reacted with one or more molar equivalents of tetrazole and di-tert-butyl N,N-diethylphosporamidate in THF at room temperature followed by addition of one or more molar equivalents of meta-chlorobenzoic acid at xe2x88x9240xc2x0 C. according to the procedure of J. W. Perich and R. B. Johns, Synthesis, 1988, 142-144) to afford the phosphate diesters of formula (Is: R4 is P(O)(OtBu)2; B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O). These phosphate diesters are then treated with one or more molar equivalents hydrochloric acid in a suitable solvent such as dioxane to provide the phosphonic acids of formula (Is: R4 is P(O)(OH)2; B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O).
The phenols of formula (Ir: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) can be transformed to the carboxylic acids of formula (Is: R4 is C(CH3)2CO2H; B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) by treatment of the phenols with two or more molar equivalents of solid sodium hydroxide followed by one or more molar equivalents of 1,1,1-trichloro-2-methyl-2-propanol tetrahydrate in the presence of a large excess of acetone which also serves as solvent.
The phenols of formula (Ir: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) can be transformed to the carboxylic acids of formula (Is: R4 is CH2CH2CO2H; B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) by treatment with one or more molar equivalents of xcex2-propiolactone and treatment with one or more molar equivalents of potassium tert-butoxide in a suitable solvent such as THF.
The phenols of formula (Ir: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) can be reacted with a 3-hydroxy carboxylic acid ester of formula CH(OH)(R7)CH2CO2R6 (R7 is H or alkyl of 1-6 carbon atoms; R6 is alkyl of 1-6 carbon atoms) to afford the esters of formula (Is: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) under the conditions of the Mitsunobu Reactions (for a review see Oyo Mitsunobu Synthesis 1981, 1-27). The other co-reagents necessary to effect the Mitsunobu Reaction include one or more molar equivalents of a alkyl of 1-6 carbon atoms azodicarboxylate diester such as diethyl azodicarboxylate or diisopropyl azodicarboxylate and one or more molar equivalents of triarylphosphine such as triphenylphosphine in a suitable solvent such as diethyl ether, THF, benzene or toluene at temperatures ranging from xe2x88x9220xc2x0 C. to 120xc2x0 C. at temperatures ranging from xe2x88x9220xc2x0 C. to 120xc2x0 C.
The 3-hydroxy carboxylic acid ester of formula CH(OH)(R7)CH2CO2R6 (R7 is H or alkyl of 1-6 carbon atoms; R6 is alkyl of 1-6 carbon atoms) are commercially available or can be prepared from commercially available carboxylic acid precursors under standard esterification conditions.
The esters of formula (Is: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) can be transformed to the acids of formula (Is: R4 is (R)-CH(R7)CH2CO2H; B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) by several standard conditions which include reacting the ester of formula (Is) with two or more molar equivalents of a mineral acid such as HCl or sulfuric acid in one or more solvents or a combination of two or more solvents such as water, THF or dioxane at temperatures ranging from 40 to 120xc2x0 C. Still alternatively, many other conditions may be employed to effect the above mentioned ester to acid transformation leading to (Is). These include reacting the esters of formula (Is) with two or more molar equivalents of boron tribromide or boron trichloride in dichloromethane at xe2x88x9278xc2x0 C. to room temperature; two or more molar equivalents hydrobromic acid in acetic acid at 0xc2x0 C. to 50xc2x0 C.; two or more molar equivalents trimethylsilylbromide or trimethylsilyliodide in dichloromethane, carbon tetrachloride or acetonitrile at xe2x88x9278xc2x0 C. to 50xc2x0 C.; two or more molar equivalents lithium iodide in pyridine or quinoline at temperatures from 60xc2x0 to 250xc2x0 C.
The nitrophenols of formula (Ir: B is NO2; D is H or Br; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; Y is H, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) can be alkylated with one or more molar equivalents of an alkyl or aralkyl halide of formula (XR4 where X is Cl, Br or I and R4 is alkyl of 1-6 carbon atoms, aralkyl ) and with one or more molar equivalents of an alkali metal carbonate such as potassium carbonate in a polar aprotic solvent such as DMF to afford the alkylated product of formula (Is: B is NO2; D is H or Br; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; Y is H, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O; R4 is alkyl of 1-6 carbon atoms, aralkyl).
The nitro compounds of formula (Is: B is NO2; D is H or Br; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; Y is H, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O; R4 is alkyl of 1-6 carbon atoms, aralkyl) can be reduced to the amino compounds of formula (Is: B is NH2; D is H or Br; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; Y is H, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O; R4 is alkyl of 1-6 carbon atoms, aralkyl) most readily using tin dichloride in ethylacetate at 40 to 100xc2x0 C. or with hydrazine and Montmorillinite clay in ethanol at 40 to 100xc2x0 C.
The amino compounds of formula (Is: B is NH2; D is H or Br; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; Y is H, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O; R4 is alkyl of 1-6 carbon atoms, aralkyl) can be alkylated with one or more molar equivalents of an alkyl haloacetate of formula (X2CHR6aCO2R6 where X2 is Cl, Br or I and R6 is alkyl of 1-6 carbon atoms, R6a is H) and with one or more molar equivalents of an alkali metal carbonate such as potassium carbonate in a polar aprotic solvent such as DMF to afford the alkylated product of formula (Is: B is NCHR6aCO2R6; R6 is alkyl of 1-6 carbon atoms; R6a is H or alkyl of 1-6 carbon atoms; D is H or Br; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; Y is H, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O; R4 is alkyl of 1-6 carbon atoms, aralkyl). These esters can be transformed into their carboxylic acid analogs using standard conditions to afford the carboxylic acids of formula (Is: B is NCHR6aCO2H; R6a is H or alkyl of 1-6 carbon atoms; D is H or Br; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; Y is H, OR1, SR1, NR1R2, where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O; R4 is alkyl of 1-6 carbon atoms, aralkyl). The conditions to effect these transformations include aqueous base in which one or more molar equivalents of alkali metal hydroxide such as sodium hydroxide is used in water with a co-solvent such as THF, dioxane or a lower alcohol such as methanol or mixtures of THF and a lower alcohol at temperatures ranging from 0xc2x0 C. to 40xc2x0 C. 
Further derivatives of the compounds of formula (I) in Scheme 11 can be prepared by the following methods. The compounds of formula (It: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro; Y is Cl, Br, ORxe2x80x2 where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; R5 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; R6 is H, alkyl of 1-6 carbon atoms) can be transformed into their sulfoxide derivatives of formula (Iu: n is 1; B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro; Y is Cl, Br, OR1 where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; R5 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; R6 is H, alkyl of 1-6 carbon atoms) using one molar equivalent of an oxidizing agent such as m-chloroperbenzoic acid in dichloromethane at temperatures ranging from xe2x88x9220xc2x0 C. to 40xc2x0 C. or peracetic aid in acetic acid and water at temperatures ranging from room temperature to 100xc2x0 C.
The compounds of formula (It: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro; Y is Cl, Br, OR1 where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; Rxe2x80x2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; R6 is H, alkyl of 1-6 carbon atoms) can be transformed into their sulfone derivatives of formula (Iu: n is 2; B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro; Y is Cl, Br, OR1 where R1, R2 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; R5 is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; R6 is H, alkyl of 1-6 carbon atoms) using two or more molar equivalents of an oxidizing agent such as m-chloroperbenzoic acid in dichloromethane at temperatures ranging from xe2x88x9220xc2x0 C. to 60xc2x0 C. or peracetic aid in acetic acid and water at temperatures ranging from room temperature to 100xc2x0 C.
The compounds of this invention are useful in treating metabolic disorders related to insulin resistance or hyperglycemia, typically associated with obesity or glucose intolerance. The compounds of this invention are therefore, particularly useful in the treatment or inhibition of type II diabetes. The compounds of this invention are also useful in modulating glucose levels in disorders such as type I diabetes.
The ability of compounds of this invention to treat or inhibit disorders related to insulin resistance or hyperglycemia was established with representative compounds of this invention in the following two standard pharmacological test procedures which measure the inhibition of PTPase.
Inhibition of Tri-Phosphorylated Insulin Receptor Dodecaphosphopeptide Dephosphorylation by Rat Hepatic Protein-Tyrosine Phosphatases (PTPases)
This standard pharmacological test procedure assess the inhibition of rat hepatic microsomal PTPase activity using, as substrate, the phosphotyrosyl dodecapeptide corresponding to the 1142-1153 insulin receptor kinase domain, phosphorylated on the 1146, 1150 and 1151 tyrosine residues. The procedure used and results obtained are briefly outlined below.
Preparation of Microsomal Fraction: Rats (Male Sprague-Dawley rats (Charles River, Kingston, N.Y.) weighing 100-150 g, maintained on standard rodent chow (Purina)) are sacrificed by asphyxiation with CO2 and bilateral thoracotomy. The liver is removed and washed in cold 0.85% (w/v) saline and weighed. The tissue is homogenized on ice in 10 volumes of Buffer A and the microsomes are isolated essentially as described by Meyerovitch J, Rothenberg P, Shechter Y, Bonner-Weir S, Kahn C R. Vanadate normalizes hyperglycemia in two mouse models of non-insulin-dependent diabetes mellitus. J Clin Invest 1991; 87:1286-1294 and Alberts B, Bray D, Lewis J, Raff M, Roberts K, Watson J D, editors. Molecular biology of the cell. New York: Garland Publishing, Inc., 1989 with minor modifications. The liver homogenate is filtered through silk to remove any remaining tissue debris and then is centrifuged at 10,000xc3x97g for 20 minutes at 40C. The supernatant is decanted and centrifuged at 100,000xc3x97g for 60 minutes at 40C. The pellet, microsomes and small vesicles, is resuspended and lightly homogenized in: 20 mM TRIS-HCl (pH 7.4), 50 mM 2-mercaptoethanol, 250 mM sucrose, 2 mM EDTA, 10 mM EGTA, 2 mM AEBSF, 0.1 mM TLCK, 0.1 mM TPCK, 0.5 mM benzamidine, 25 ug/ml leupeptin, 5 ug/ml pepstatin A, 5 ug/ml;H5B antipain, 5 ug/ml chymostatin, 10 ug/mil aprotinin (Buffer A), to a final concentration of approximately 850 ug protein/ml. Protein concentration is determined by the Pierce Coomassie Plus Protein Assay using crystalline bovine serum albumin as a standard (Pierce Chemical Co., Rockford, Ill.).
Measurement of PTPase activity: The malachite green-ammonium molybdate method, as described by Lanzetta P A, Alvarez L J, Reinach P S, Candia O A was used. An improved assay for nanomolar amounts of inorganic phosphate. Anal. Biochem. 1979;100:95-97, and adapted for the platereader, is used for the nanomolar detection of liberated phosphate by rat hepatic microsomal PTPases. The test procedure uses, as substrate, a dodecaphosphopeptide custom synthesized by AnaSpec, Inc. (San Jose, Calif.). The peptide, TRDIYETDYYRK, corresponding to the 1142-1153 catalytic domain of the insulin receptor, is tyrosine phosphorylated on the 1146, 1150 and 1151 tyrosine residues. The microsomal fraction (83.25 ul) is preincubated for 10 min at 37 deg.C with or without test compound (6.25 ul) and 305.5 ul of the 81.83 mM HEPES reaction buffer, pH 7.4. Peptide substrate, 10.5 ul at a final concentration of 50 uM, is equilibrated to 37 deg.C in a LABLINE Multi-Blok heater equipped with a titerplate adapter. The preincubated microsomal preparation (39.5 ul) with or without drug is added to initiate the dephosphorylation reaction, which proceeds at 37 deg.C for 30 min. The reaction is terminated by the addition of 200 ul of the malachite green-ammonium molybdate-Tween 20 stopping reagent (MG/AM/Tw). The stopping reagent consists of 3 parts 0.45% malachite green hydrochloride, 1 part 4.2% ammonium molybdate tetrahydrate in 4 N HCl and 0.5% Tween 20. Sample blanks are prepared by the addition of 200 ul MG/AM/Tw to substrate and followed by 39.5 ul of the preincubated membrane with or without drug. The color is allowed to develop at room temperature for 30 min and the sample absorbances are determined at 650 nm using a platereader (Molecular Devices). Samples and blanks are prepared in quadruplicates. Screening activity of 50 uM (final) drug is accessed for inhibition of microsomal PTPases.
Calculations: PTPase activities, based on a potassium phosphate standard curve, are expressed as nmoles of phosphate released/min/mg protein. Test compound PTPase inhibition is calculated as percent of control. A four parameter non-linear logistic regression of PTPase activities using SAS release 6.08, PROC NLIN, is used for determining IC50 values of test compounds. All compounds were administered at a concentration of 50 xcexcM. The following results were obtained using representative compounds of this invention.
Inhibition of Tri-Phosphorylated Insulin Receptor Dodecaphosphopeptide Dephosphorylation by hPTP1B
This standard pharmacological test procedure assess the inhibition of recombinant rat protein phosphatase, PTP1B, activity using, as substrate, the phosphotyrosyl dodecapeptide corresponding to the 1142-1153 insulin receptor kinase domain, phosphorylated on the 1146, 1150 and 1151 tyrosine residues. The procedure used and results obtained are briefly described below.
Human recombinant PTP1B was prepared as described by Goldstein (see Goldstein et al. Mol. Cell. Biochem. 109, 107, 1992). The enzyme preparation used was in microtubes containing 500-700 xcexcg/ml protein in 33 mM Tris-HCl, 2 MM EDTA, 10% glycerol and 10 mM 2-mercaptoethanol.
Measurement of PTPase activity. The malachite green-ammonium molybdate method, as described (Lanzetta et al. Anal. Biochem. 100, 95, 1979) and adapted for a platereader, is used for the nanomolar detection of liberated phosphate by recombinant PTP1B. The test procedure uses, as substrate, a dodecaphosphopeptide custom synthesized by AnaSpec, Inc. (San Jose, Calif.). the peptide, TRDIYETDYYRK, corresponding to the 1142-1153 catalytic domain of the insulin receptor, is tyrosine phosphorylated on the 1146, 1150, and 1151 tyrosine residues. The recombinant rPTP1B is diluted with buffer (pH 7.4, containing 33 mM Tris-HCl, 2 mM EDTA and 50 mM b-mercaptoethanol) to obtain an approximate activity of 1000-2000 nmoles/min/mg protein. The diluted enzyme (83.25 mL) is preincubated for 10 min at 37xc2x0 C. with or without test compound (6.25 mL) and 305.5 mL of the 81.83 mM HEPES reaction buffer, pH 7.4 peptide substrate, 10.5 ml at a final concentration of 50 mM, and is equilibrated to 37xc2x0 C. in a LABLINE Multi-Blok heater equipped with a titerplate adapter. The preincubated recombinant enzyme preparation (39.5 ml) with or without drug is added to initiate the dephosphorylation reaction, which proceeds at 37xc2x0 C. for 30 min. The reaction is terminated by the addition of 200 mL of the malachite green-ammonium molybdate-Tween 20 stopping reagent (MG/AM/Tw). The stopping reagent consists of 3 parts 0.45% malachite green hydrochloride, 1 part 4.2% ammonium molybdate tetrahydrate in 4 N HCl and 0.5% Tween 20. Sample blanks are prepared by the addition of 200 mL MG/AM/Tw to substrate and followed by 39.5 ml of the preincubated recombinant enzyme with or without drug. The color is allowed to develop at room temperature for 30 min. and the sample absorbances are determined at 650 nm using a platereader (Molecular Devices). Sample and blanks are prepared in quadruplicates.
Calculations: PTPase activities, based on a potassium phosphate standard curve, are expressed as nmoles of phosphate released/min/mg protein. Inhibition of recombinant PTP1B by test compounds is calculated as percent of phosphatase control. A four parameter non-linear logistic regression of PTPase activities using SAS release 6.08, PROC NLIN, is used for determining IC50 values of test compounds. The following results were obtained.
The blood glucose lowering activity of representative compounds of this invention were demonstrated in an in vivo standard procedure using diabetic (ob/ob) mice. The procedures used and results obtained are briefly described below.
The non-insulin dependent diabetic (NIDDM) syndrome can be typically characterizes by obesity, hyperglycemia, abnormal insulin secretion, hyperinsulinemia and insulin resistance. The genetically obese-hyperglycemic ob/ob mouse exhibits many of these metabolic abnormalities and is thought to be a useful model to search for hypoglycemic agents to treat NIDDM [Coleman, D.: Diabetologia 14: 141-148, 1978].
In each test procedure, mice [Male or female ob/ob (C57 B1/6J) and their lean litermates (ob/+ or +/+, Jackson Laboratories) ages 2 to 5 months (10 to 65 g)] of a similar age were randomized according to body weight into 4 groups of 10 mice. The mice were housed 5 per cage and are maintained on normal rodent chow with water ad libitum. Mice received test compound daily by gavage (suspended in 0.5 ml of 0.5% methyl cellulose); dissolved in the drinking water; or admixed in the diet. The dose of compounds given ranges from 2.5 to 200 mg/kg body weight/day. The dose is calculated based on the fed weekly body weight and is expressed as active moiety. The positive control, ciglitazone (5-(4-(1-methylcyclohexylmethoxy)benzyl)-2,4-dione, see Chang, A., Wyse, B., Peterson, T. and Diani, A. Diabetes 32: 830-838, 1983.) was given at a dose of 100 mg/kg/day, which produces a significant lowering in plasma glucose. Control mice received vehicle only.
On the morning of Day 4, 7 or 14 two drops of blood (approximetly 50 ul) were collected into sodium fluoride containing tubes either from the tail vein or after decapitation. For those studies in which the compound was administered daily by gavage the blood samples were collected 0 and 4 hours after compound administration. The plasma was isolated by centrifugation and the concentration of glucose is measured enzymatically on an Abbott V. P. Analyzer.
For each mouse, the percentage change in plasma glucose on Day 4, 7 or 14 is calculated relative to the mean plasma glucose of the vehicle treated mice. Analysis of variance followed by Dunett""s Comparison Test (one-tailed) are used to estimate the significant difference between the plasma glucose values from the control group and the individual compound treated groups (CMS SAS Release 5.18).
The results shown in the table below shows that the compounds of this invention are antihyperglycemic agents as they lower blood glucose levels in diabetic mice.
Based on the results obtained in the standard pharmacological test procedures, representative compounds of this invention have been shown to inhibit PTPase activity and lower blood glucose levels in diabetic mice, and are therefore useful in treating metabolic disorders related to insulin resistance or hyperglycemia, typically associated with obesity or glucose intolerance. More particularly, the compounds of this invention useful in the treatment or inhibition of type II diabetes, and in modulating glucose levels in disorders such as type I diabetes. As used herein, the term modulating means maintaining glucose levels within clinically normal ranges.
Effective administration of these compounds may be given at a daily dosage of from about 1 mg/kg to about 250 mg/kg, and may given in a single dose or in two or more divided doses. Such doses may be administered in any manner useful in directing the active compounds herein to the recipient""s bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, vaginally, and transdermally. For the purposes of this disclosure, transdermal administrations are understood to include all administrations across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administrations may be carried out using the present compounds, or pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).
Oral formulations containing the active compounds of this invention may comprise any conventionally used oral forms, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions. Capsules may contain mixtures of the active compound(s) with inert fillers and/or diluents such as the pharmaceutically acceptable starches (e.g. corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses, such as crystalline and microcrystalline celluloses, flours, gelatins, gums, etc. Useful tablet formulations may be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starches and powdered sugar. Oral formulations herein may utilize standard delay or time release formulations to alter the absorption of the active compound(s). Suppository formulations may be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository""s melting point, and glycerin. Water soluble suppository bases, such as polyethylene glycols of various molecular weights, may also be used.
It is understood that the dosage, regimen and mode of administration of these compounds will vary according to the malady and the individual being treated and will be subject to the judgment of the medical practitioner involved. It is preferred that the administration of one or more of the compounds herein begin at a low dose and be increased until the desired effects are achieved.